The long-term goal of this project is to develop and evaluate new single photon emission computed tomography (SPECT) imaging configurations for improved characterization and quantification of radiopharmaceutical uptake in early-stage breast cancer. The configurations include: i)conventional, large field of view (FOV) cameras equipped with either pinhole (PinH) or convergent beam (CvB) collimators and ii) novel, medium FOV tiltable cameras, equipped with either PinH collimation, CvB, or combined PinH (or CvB) and tilted-parallel beam collimation. These cameras revolve around a center of rotation located within a pendulous, prone-dependent breast. The main hypothesis of this project is that characterization and quantification of radiopharmaceutical uptake in small tumors (<8 mm dia., 6:1 uptake) during early-stage breast cancer can be achieved by combining: i) appropriate three-dimensional (3D) orbital configurations utilizing available and/or novel nuclear medicine SPECT cameras; ii) PinH, CvB or combined collimator configurations; and iii) improved reconstruction algorithms. It is not a goal of this proposal to evaluate the performance of currently available radiopharmaceuticals used for breast cancer imaging, nor is it a goal to develop a SPECT system to perform routine screening for breast tumor detection. Advantages of the proposed designs include: i) minimal radius of rotation by using PinH collimators on large FOV cameras and/or compact cameras; ii) improved system sensitivity and resolution due to the potential use of multiple specially designed cameras and collimators; iii) reduced photon attenuation due to dedicated breast imaging orbits; and iv) tiltable cameras to extend the imaged region to include the axillary tail of the breast. Guided by the results of the first project period, the next project period in Years 5 - 8 includes the following Specific Aims: i)Investigate PinH and tilted vertical-axis-of-rotation CvB collimator configurations using available clinical SPECT systems for dedicated breast-tumor imaging; ii) Develop and evaluate novel 3D PinH and CvB orbits that sufficiently sample, or nearly sufficiently sample, the breast, including its axillary tail; iii) Develop, in collaboration with Jefferson Laboratory (JLab), a dedicated SPECT breast-imaging camera that performs tilted-camera, 3D PinH and CvB orbits and serves as a test-gantry for acquisition of combined PinH (or possibly CB)/ParH SPECT projection data. The iterative reconstruction programs developed during the initial project period will be enhanced to include modeling spatially varying resolution of PinH and cone beam CvB collimators.